Alkyl cellulose for use in tableting and solid preparation comprising same

ABSTRACT

Provided are an alkyl cellulose excellent in formability when added even in a small amount and not causing marked delay in disintegration; a solid preparation comprising it; and a method for producing the solid preparation. More specifically, provided are an alkyl cellulose for use in tableting, the alkyl cellulose having a specific surface area of from 0.5 to 10.0 m2/g as measured by BET method and a solid preparation comprising the alkyl cellulose. Also provided is a method for producing the alkyl cellulose, comprising the steps of: bringing pulp into contact with an alkali metal hydroxide solution to obtain alkali cellulose, reacting the alkali cellulose with an etherifying agent to obtain a first alkyl cellulose, pulverizing the first alkyl cellulose, and depolymerizing the pulverized first alkyl cellulose through hydrolysis with an acid catalyst or through oxidative decomposition with an oxidant to obtain a second alkyl cellulose.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.15/622,354, filed Jun. 14, 2017, which is a divisional of U.S.application Ser. No. 14/880,755, filed Oct. 12, 2015, which claimspriority from Japanese Application No. 2014-216429, filed Oct. 23, 2014,the entire contents of which are incorporated herein by reference.

FIELD

The present invention relates to, in pharmaceutical and food fields, analkyl cellulose exhibiting high formability when added even in a smallamount and a solid preparation comprising the alkyl cellulose.

BACKGROUND

In pharmaceutical and food fields, examples of a method of producing asolid preparation, particularly a tablet, include a dry direct tabletingmethod comprising the steps of mixing a drug and an additive andtableting the resulting mixture as it is, and a wet granulationtableting method comprising the steps of granulating a mixture of a drugand an additive in the presence of a binder solution or a proper solventsuch as water, drying the resulting granules, and tableting the driedgranules. When the drug or the additive has poor fluidity or formabilityin the dry direct tableting method, for example, a dry granulationtableting method comprising the steps of subjecting the mixture to rollcompression (dry granulation), crushing and then tableting may beemployed. In the wet granulation tableting method, an agitatinggranulator or a fluidized bed granulator may be used.

The dry direct tableting method has been employed frequently in recentyears because it can be used even when a drug is sensitive to water orbecause its simple process facilitates process control. However,compared with the wet granulation tableting method, the dry directtableting method usually requires a larger amount of the additive inorder to secure formability. Examples of the additive having highformability include crystalline cellulose having high formability (JP06-316535A), hydroxyalkyl cellulose fine particles (WO 2011/065350A),and low-substituted hydroxypropyl cellulose having high formability andhigh fluidity (JP 2010-254756A).

On the other hand, there is a recent tendency of reducing the size oftablet to make it easier to swallow and therefore decreasing an amountof additive such as a binder. Accordingly, a binder capable of enhancingthe hardness of the tablet when added even in a small amount isdemanded.

SUMMARY

The additive described in JP 06-316535A, however, cannot be used for asolid preparation or small-sized tablet having high drug content becausethe amount of the additive has to be increased to secure formability.The additive described in WO 2011/065350A is excellent in formabilitybut inferior in disintegration. The additive described in JP2010-254756A is excellent in disintegration but does not havesatisfactory formability. Thus, in the conventional technology, it isdifficult to secure high formability without sacrificing disintegrationwhen the amount of the additive is small.

With the foregoing in view, the invention has been made. An object ofthe invention is to provide an alkyl cellulose which is excellent informability even when a small amount thereof is added and which does notremarkably delay disintegration; a solid preparation comprising thealkyl cellulose; and a method for producing the solid preparation.

With a view to achieving the above-mentioned object, the presentinventors have proceeded with an extensive investigation. As a result,it has been found that the object can be achieved by using the alkylcellulose having a specified specific surface area, leading tocompletion of the invention.

In an aspect of the invention, there are provided an alkyl cellulose foruse in tableting, the alkyl cellulose having a specific surface area offrom 0.5 to 10.0 m²/g as measured by the BET method and a solidpreparation comprising the alkyl cellulose for use in tableting. Inanother aspect of the invention, there is also provided a method forproducing an alkyl cellulose for use in tableting, the alkyl cellulosehaving a specific surface area of from 0.5 to 10.0 m²/g as measured bythe BET method, and the method comprising the steps of: bringing pulpinto contact with an alkali metal hydroxide solution to obtain alkalicellulose, reacting the alkali cellulose with an etherifying agent toobtain a first alkyl cellulose, pulverizing g the first alkyl cellulose,and depolymerizing the pulverized first alkyl cellulose throughhydrolysis in the presence of an acid catalyst or through oxidativedecomposition in the presence of an oxidant to obtain a second alkylcellulose. In a further aspect of the invention, there is also provideda method for producing a solid preparation comprising: respective stepsof the method for producing an alkyl cellulose for use in tableting anda step of tableting a mixture or granulated product comprising a drugand the produced alkyl cellulose for use in tableting by a dry directtableting method or a dry granulation tableting method.

According to the present invention, since the alkyl cellulose exhibitshigh formability, the alkyl cellulose can enhance tablet hardness whentablets are produced by a dry direct tableting method or a drygranulation tableting method. In particular, it is effective for aformulation in which the amount of an additive is limited, for example,a formulation in which drug content should be increased; a formulationfor a small-sized tablet; or a formulation for a granule-containingtablet which has to be produced at a low tableting pressure. Inaddition, since the alkyl cellulose exhibits high formability, flakesare available in a high yield during dry granulation, and the resultingflakes is re-pulverized to produce granules or fine granules in thepresence of a reduced amount of fine powder.

DETAILED DESCRIPTION

The invention will hereinafter be described more specifically.

The alkyl cellulose has a specific surface area, as measured by the BET(BET multipoint) method, of from 0.5 to 10.0 m²/g, preferably from 0.5to 7.0 m²/g, more preferably from 1.0 to 7.0 m²/g, still more preferablyfrom 1.2 to 7.0 m²/g, particularly preferably 1.2 to 2.0 m²/g. An alkylcellulose having a specific surface area of less than 0.5 m²/g cannotexhibit desired formability. An alkyl cellulose having a specificsurface area of more than 10.0 m²/g has deteriorated miscibility with adrug or deteriorated fluidity during production of a tablet.

The specific surface area can be analyzed using the BET (BET multipoint)method, being based on low-temperature low-humidity physical adsorptionof an inert gas, and comprising the step of adsorbing a molecule havinga known adsorption occupation area on the surfaces of sample powderparticles at a temperature of liquid nitrogen for determining thespecific surface area of the sample from the adsorption amount. It canbe measured, for example, in accordance with “Method 2: The volumetricmethod” of “Specific Surface Area by Gas Adsorption” in General Testsdescribed in the Japanese Pharmacopoeia 16th Edition by using anautomated specific surface area and pore distribution analyzer “TriStarII 3020” (product of Micromeritics).

The viscosity at 20° C. of a 2% by weight aqueous solution of the alkylcellulose is preferably from 1 to 15 mPa·s, more preferably from 2 to 8mPa·s, still more preferably from 2 to 6 mPa·s, particularly preferablyfrom 2.5 to 4.5 mPa·s. An alkyl cellulose having a viscosity of lessthan 1 mPa·s may not be obtained easily in the depolymerization step. Analkyl cellulose having a viscosity of more than 15 mPa·s may have poordisintegration and also have poor formability so that it may not havetablet hardness enhanced.

As described in JP 06-316535A or WO 2011/065350A, it is known that apolymer having a lower polymerization degree (i.e. a lower viscosity)usually has lower formability. However, the present inventors have foundthat surprisingly, an alkyl cellulose having a lower polymerizationdegree is superior in formability. It is presumed that an alkylcellulose having a lower viscosity, that is, a lower polymerizationdegree, is apt to undergo rearrangement of molecular chains so that easyplastic deformation thereof during compression improves formability, andincreases tablet hardness.

When the viscosity at 20° C. of a 2% by weight aqueous solution of thealkyl cellulose is equal to or more than 600 mPa·s, it can be measuredusing a rotational viscometer in accordance with “ViscosityDetermination” in General Tests described in the Japanese Pharmacopoeia16th Edition. When the viscosity at 20° C. of a 2% by weight aqueoussolution of the alkyl cellulose is less than 600 mPa·s, it can bemeasured using an Ubbelohde-type viscometer in accordance with“Viscosity measurement by capillary tube viscometer” in General Testsdescribed in the Japanese Pharmacopoeia 16th Edition.

The alkyl cellulose has an average particle size of preferably from 1 to120 μm, more preferably from 1 to 70 μm, still more preferably from 10to 70 μm, still more preferably from 10 to 50 μm, particularlypreferably from 10 to 30 μm. An alkyl cellulose having an averageparticle size of less than 1 μm may have deteriorated miscibility with adrug or deteriorated fluidity during production of tablets. An alkylcellulose having an average particle size of more than 120 μm may notsecure an adequate specific surface area so that it may not have desiredformability.

The average particle size is a volume-based average particle size and asdescribed, for example, in page 88 of “Kaitei Zoho Funtai Bussei Zusetsu(revised and enlarged edition, Physical Properties of Powder withIllustrations” edited by The Society of Powder Technology, Japan, andThe Association of Powder Process Industry and Engineering, JAPAN,published by Nikkei Gijutsu Tosho Co., Ltd., 1985, it is calculatedusing the formula: {Σ(nD³)/Σn}^(1/3), wherein D is a particle diameter,n is the number of particles having the particle diameter, and Σn is atotal number of particles. The term “D₅₀” means a particle size (i.e.average particle size) when the cumulative particle-size distribution is50%. The average particle size can be measured using a dry laserdiffraction method. For example, a volume-based average particle sizecan be determined from a diffraction intensity obtained by irradiating alaser light to a powder sample jetted by compressed air, as in themethod using “Mastersizer 3000” (trade name) of MalvernInstruments/England or HELOS system of Sympatec GmbH/Germany.

The alkyl cellulose has a loose bulk density of preferably from 0.01 to0.50 g/mL, more preferably from 0.03 to 0.50 g/mL, still more preferablyfrom 0.1 to 0.50 g/mL, still more preferably from 0.2 to 0.4 g/mL. Analkyl cellulose having a loose bulk density of less than 0.01 g/mL mayhave deteriorated miscibility with a drug or deteriorated fluidityduring production of tablets. An alkyl cellulose having a loose bulkdensity of more than 0.5 g/mL may have deteriorated formability.

The term “loose bulk density” means a bulk density in a loosely filledstate and is determined by the method comprising the steps of: allowinga sample to pass through JIS 22-mesh sieve (opening: 710 μm), uniformlyfeeding the sample into a cylindrical vessel being made of a stainlesssteel and having a diameter of 5.03 cm and a height of 5.03 cm(capacity: 100 ml) from 23 cm above the vessel, leveling off the topsurface of the sample, and then weighing the remaining sample.

The alkyl cellulose is a nonionic polymer in which one or more of thehydroxyl groups on the glucose ring of the cellulose have beenetherified. Examples of the alkyl cellulose include methyl cellulose andethyl cellulose. Of these, methyl cellulose is particularly preferredfrom the standpoint of formability and disintegration.

The degree of substitution of the alkyl cellulose is not particularlylimited. For example, methyl cellulose has the degree of methoxysubstitution of preferably from 26.0 to 33.0% by weight, more preferablyfrom 27.5 to 31.5% by weight. The degree of methoxy substitution can bemeasured using a method based on the determination method of the degreeof substitution of methyl cellulose described in The JapanesePharmacopoeia 16th Edition.

Examples of a substance analogous to the alkyl cellulose includehydroxyalkylalkyl celluloses such as hydroxypropylmethyl cellulose. Thepresent inventors have found that a tablet comprising the alkylcellulose in accordance with the invention has a shorter disintegrationtime than the tablet comprising a hydroxyalkylalkyl cellulose.

It is generally known that when a tablet containing a water-solublepolymer disintegrates by the saliva, water or the like in the oralcavity, the water-soluble polymer dissolves therein to generateviscosity for preventing water from penetrating into the tablet, therebydelaying the disintegration time. Methyl cellulose andhydroxypropylmethyl cellulose are insoluble in a high temperaturesolvent, but become soluble as the solvent temperature decreases.Hydroxypropylmethyl cellulose dissolves at 50° C. or lower, whileaccording to invention, the alkyl cellulose such as methyl cellulose hasno hydroxyalkyl group so that a dissolution temperature thereof is lowerthan that of the hydroxyalkylalkyl cellulose. It is therefore presumedthat since the alkyl cellulose does not dissolve in a test solution ofbody temperature equivalent 37° C. at which disintegration time oftablets is measured, the alkyl cellulose does not generate viscosity,thereby not delaying the disintegration time.

Next, a solid preparation comprising the alkyl cellulose will beexplained.

Since the alkyl cellulose has high formability, addition of the alkylcellulose even in a small amount can enhance the tablet hardness whentablets are produced by the dry direct tableting method or the drygranulation tableting method. The meaning of the term “small” in the“small amount” differs depending on the weight or shape of the tablet ora kind of the drug contained therein. The alkyl cellulose content in thesolid preparation is preferably 20% by weight or less, more preferably10% by weight or less, still more preferably 5% by weight or less. Whenthe alkyl cellulose content is more than 20% by weight, a disintegrationtime may be deteriorated although tablet hardness may increase. Thelower limit of the alkyl cellulose content differs depending on theweight or shape of the tablet or a kind of the drug contained therein.The alkyl cellulose content is preferably 0.1% by weight or more, morepreferably 1% by weight or more. When the content is below 0.1% byweight, desired formability may not be achieved.

Next, a method for producing the alkyl cellulose will be described.

Pulp and an alkali metal hydroxide solution are brought into contactwith each other in a conventional method to obtain an alkali cellulose.The pulp may be in sheet form or chip form. The pulp is preferably inpowder form obtained by pulverization with a pulverizer. The step ofbringing pulp into contact with an alkali metal hydroxide solution ispreferably carried out in a reactor having an internal stirringstructure.

The alkali cellulose thus obtained is reacted with an etherifying agentin a conventional method to obtain a first (high-polymerization-degree,pre-depolymerization) alkyl cellulose.

The etherifying agent useful for producing the first alkyl cellulose isknown and not particularly limited. Examples of the etherifying agentinclude an alkylating agent such as methyl chloride.

The first alkyl cellulose obtained by the etherification reaction may beoptionally purified or dried in a conventional method.

A purification method or an apparatus used for the purification is notparticularly limited. It is preferably a washing method or a washingapparatus using preferably water, more preferably hot water (preferablyof from 85 to 100° C.).

A drying method or an apparatus used for drying is not particularlylimited. It is preferably a method or an apparatus capable of settingthe temperature of the first alkyl cellulose during drying at from 40 to80° C.

The viscosity at 20° C. of a 2% by weight aqueous solution of the firstalkyl cellulose obtained after the optional purification and dryingsteps is not particularly limited. It is preferably more than 20 mPa·s,more preferably from 50 to 100000 mPa·s, still more preferably from 100to 10000 mPa·s. When the viscosity at 20° C. of a 2% by weight aqueoussolution of the first alkyl cellulose is equal to or more than 600mPa·s, it can be measured using a single cylinder-type rotationalviscometer in accordance with “Viscosity measurement by rotationalviscometer” in General Tests described in the Japanese Pharmacopoeia16th Edition. When the viscosity is less than 600 mPa·s, it can bemeasured using an Ubbelohde-type viscometer in accordance with“Viscosity measurement by capillary tube viscometer” in General Testsdescribed in the Japanese Pharmacopoeia 16th Edition.

The first alkyl cellulose is, after the optional purification and dryingsteps, pulverized into particles having an average particle size ofpreferably from 1 to 200 μm, more preferably from 10 to 200 μm, stillmore preferably from 10 to 120 μm in order to satisfy the specificsurface area of the alkyl cellulose obtained as a final product. Afterthe pulverization, the resulting particles may be optionally classifiedthrough a sieve having a predetermined opening size to control thespecific surface area.

A pulverization method or an apparatus to be used for the pulverizationis not particularly limited. Examples of the apparatus preferablyinclude an impact grinder such as “Turbo Mill” (product of Turbo Kogyo),“PPSR” (product of Pallmann Industries), “Victory Mill” (product ofHosokawa Micron), “Jet Mill” (product of Nippon Pneumatic), “ACMPulverizer” (product of Hosokawa Micron) and “Micron Jet” (product ofHosokawa Micron), and a compaction grinder such as a vibration mill, aball mill, a roller mill and a beads mill from the standpoint ofobtaining a high specific surface area.

Next, the first alkyl cellulose is depolymerized to obtain a second(low-polymerization-degree, post-depolymerization) alkyl cellulose.Further improvement in formability can be expected from thedepolymerization of decreasing a polymerization degree. Thedepolymerization may be carried out through hydrolysis in the presenceof an acid catalyst or through oxidative decomposition in the presenceof an oxidant. It is preferably carried out through hydrolysis inpresence of an acid catalyst.

Preferred examples of an acid to be used for the depolymerizationthrough hydrolysis in the presence of an acid catalyst include aninorganic acid such as hydrochloric acid, sulfuric acid, nitric acid andphosphoric acid. The acid may be used alone or in combination of two ormore.

The acid to be added to the system may be in a gas form or a solutionform. It is preferably in a solution form. The weight of the acid to beadded is from 0.1 to 3.0% by weight, preferably from 0.15 to 1.5% byweight relative to the weight of the alkyl cellulose.

An internal temperature during the depolymerization is not particularlylimited. It is preferably from 50 to 130° C., more preferably from 60 to110° C., still more preferably from 60 to 90° C. The depolymerizationtime is preferably selected in consideration of the respectiveviscosities at 20° C. of 2% by weight aqueous solutions of the firstalkyl cellulose (i.e. the pre-depolymerization alkyl cellulose) and thesecond alkyl cellulose (i.e. the post-depolymerization alkyl cellulose),and depolymerization operation conditions.

The viscosity of the 2% by weight aqueous solution of the second alkylcellulose thus obtained after depolymerization is preferably from 1 to15 mPa·s.

When the second alkyl cellulose thus obtained has a specific surfacearea outside the range of the invention, an alkyl cellulose having thespecific surface area of the invention can be obtained by furtherpulverizing the second alkyl cellulose. The specific surface area may becontrolled by classifying the pulverized particles, for example, througha sieve having a predetermined opening size. A pulverization method or apulverizer used for the pulverization is not particularly limited. Theabove-mentioned pulverizer or the like can be used. The sieve to be usedfor the classification is not particularly limited. The sieves such as aJIS 200-mesh sieve (opening: 75 μm), JIS 235-mesh sieve (opening: 63μm), JIS 330-mesh sieve (opening: 45 μm) and JIS 390-mesh sieve(opening: 38 μm) are preferred.

Next, a method for producing a solid preparation comprising the obtainedalkyl cellulose for use in tableting will be explained.

A solid preparation can be obtained by tableting or granulating thealkyl cellulose for use in tableting, together with a drug and a variousadditive commonly usable in this field including an excipient, adisintegrant, a binder, an aggregation-preventing agent and asolubilizing agent for a pharmaceutical compound. Examples of the solidpreparation include a tablet, a granule, a powder and a capsule. Thesolid preparation can be used as an orally disintegrating tablet, whichhas been investigated actively in recent years.

The tablet can be produced by any of a dry direct tableting method, adry granulation tableting method, a wet agitation granulation tabletingmethod and a fluidized bed granulation tableting method and others. Ofthese, the dry direct tableting method and the dry granulation tabletingmethod are particularly preferred from the standpoint of each using thealkyl cellulose without dissolution thereof.

The dry direct tableting method is the method of tableting a mixturecomprising a drug and the alkyl cellulose for use in tableting, as wellas, for example, an optional excipient, an optional disintegrant and/oran optional lubricant, the mixture having been obtained by dry mixing.The dry direct tableting method does not comprise a granulation step sothat it can simplify the manufacturing process and is a highlyproductive method.

The dry granulation tableting method is the method of tableting granulescomprising a drug and the alkyl cellulose for use in tableting, as wellas, for example, an optional excipient, an optional disintegrant and/oran optional lubricant, the granules having been obtained by compressiongranulation. The dry granulation tableting method is effective for adrug sensitive to water or a solvent. The compression granulationproduct can be obtained, for example, through roller compression using acompaction granulator such as a roller compactor. The roller pressure isvariable depending on, for example, the physical properties of thepowders. The roller pressure is preferably from 1 to 30 MPa, morepreferably from 2 to 12 MPa and the rotation speed of the roller ispreferably from 1 to 50 rpm, more preferably from 2 to 20 rpm. Therotation speed of a screw is preferably from 1 to 100 rpm, morepreferably from 2 to 50 rpm. Flakes obtained through roller compressionare subjected to pulverization and sizing by using a pulverizer orcrusher such as Comill, a quick mill or a power mill, into granuleshaving desired particle sizes for tableting.

The alkyl cellulose for tableting can also be used for orallydisintegrating tablets which have been investigated actively in recentyears.

According to the invention, a drug to be used for producing a solidpreparation comprising the alkyl cellulose is not particularly limitedinsofar as it is orally administrable. Examples of the drug includedrugs for the central nervous system, drugs for the circulatory system,drugs for the respiratory system, drugs for the digestive system,antibiotics, antitussives/expectorants, antihistamines, analgesicantipyretic anti-inflammatory drugs, diuretics, autonomic drugs,antimalarial drugs, antidiarrheal agents, psychotropic drugs, andvitamins and derivatives thereof.

Examples of the drugs for the central nervous system include diazepam,idebenone, aspirin, ibuprofen, paracetamol, naproxen, piroxicam,dichlofenac, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin,acetaminophen, ethenzamide, ketoprofen and chlordiazepoxide.

Examples of the drugs for the circulatory system include molsidomine,vinpocetine, propranolol, methyldopa, dipyridamole, furosemide,triamterene, nifedipine, atenolol, spironolactone, metoprolol, pindolol,captopril, isosorbide nitrate, delapril hydrochloride, meclofenoxatehydrochloride, diltiazem hydrochloride, etilefrine hydrochloride,digitoxin, propranolol hydrochloride and alprenolol hydrochloride.

Examples of the drugs for the respiratory system include amlexanox,dextromethorphan, theophilline, pseudo-ephedrine, salbutamol andguaiphenesin.

Examples of the drugs for the digestive system includebenzimidazole-based drugs having anti-ulcer action such as2-[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]benzimidazoleand5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole;cimetidine; ranitidine; pirenzepine hydrochloride; pancreatin;bisacodyl; and 5-aminosalicylic acid.

Examples of the antibiotics include talampicillin hydrochloride,bacampicillin hydrochloride, cephaclor and erythromycin.

Examples of the antitussives/expectorants include noscapinehydrochloride, carbetapentane citrate, dextromethorphan hydrobromide,isoaminile citrate and dimemorfan phosphate.

Examples of the antihistamines include chlorpheniramine maleate,diphenhydramine hydrochloride and promethazine hydrochloride.

Examples of the analgesic antipyretic and anti-inflammatory drugsinclude ibuprofen, diclofenac sodium, flufenamic acid, sulpyrine,aspirin and ketoprofen.

Examples of the diuretics include caffeine.

Examples of the autonomic drugs include dihydrocodeine phosphate,methylephedrine dl-hydrochloride, atropine sulfate, acetylcholinechloride and neostigmine.

Examples of the antimalarial drugs include quinine hydrochloride.

Examples of the antidiarrheal agents include loperamide hydrochloride.

Examples of the psychotropic drugs include chlorpromazine.

Examples of the vitamins and derivatives thereof include Vitamin A,Vitamin B1, fursultiamine, Vitamin B2, Vitamin B6, Vitamin B12, VitaminC, Vitamin D, Vitamin E, Vitamin K, calcium pantothenate and tranexamicacid.

Examples of the excipient include saccharides such as sucrose, lactoseand glucose; sugar alcohols such as mannitol, sorbitol and erythritol;starches; crystalline cellulose; calcium phosphate; and calcium sulfate.

Examples of the binder include polyvinyl alcohol, polyacrylic acid,polymethacrylic acid, polyvinylpyrrolidone, glucose, sucrose, lactose,maltose, dextrin, sorbitol, mannitol, macrogols, gum arabic, gelatin,agar, starches, crystalline cellulose and low-substituted hydroxypropylcellulose.

Examples of the disintegrant include low-substituted hydroxypropylcellulose, carmellose or a salt thereof, croscarmellose sodium,carboxymethyl starch sodium, crospovidone, crystalline cellulose andcrystalline cellulose carmellose sodium.

Examples of the lubricant and the aggregation-preventing agent includetalc, magnesium stearate, calcium stearate, colloidal silica, stearicacid, waxes, hydrogenated oils, polyethylene glycols and sodiumbenzoate.

Examples of the solubilizing agent for a pharmaceutical compound includeorganic acids such as fumaric acid, succinic acid, malic acid and adipicacid.

EXAMPLES

The invention will hereinafter be described more specifically on basisof Examples and Comparative Examples. However, it should not beconstrued that the invention is limited to or by Examples. There can bemodifications in various ways by those skilled in the art withoutdeparting from the technical concept of the invention.

Example 1

An internal stirring type pressure reactor was charged with 6.0 kg, interms of cellulose content, of powdery pulp. After vacuuming andnitrogen purge, 14.1 kg of a 49% by weight aqueous sodium hydroxidesolution was added thereto and stirred to obtain alkali cellulose. Then,11.9 kg of methyl chloride was added thereto and reacted to obtain amethyl cellulose reaction product. The reaction product thus obtainedwas washed, dried, ground using a high-speed rotating impact grindingmill, Victory Mill, equipped with a screen of 0.3-mm openings, andfiltered through a sieve with 150-μm openings to obtain first methylcellulose (high-polymerization-degree, pre-depolymerization). The firstmethyl cellulose had a degree of methoxy substitution of 29% by weight.

To the first (high-polymerization-degree, pre-depolymerization) methylcellulose was added a 10% by weight aqueous hydrochloric acid solutionin an amount equivalent of 0.3% by weight of HCl relative to the amountof the methyl cellulose. The internal temperature was regulated to 80°C. and depolymerization was carried out for 70 minutes to obtain second(low-polymerization-degree, post-depolymerization) methyl cellulose. Thespecific surface area, viscosity at 20° C. of a 2% by weight aqueoussolution, average particle size, and loose bulk density of the resultingpowder are shown in Table 1.

After adjustment of the water content of the second methyl cellulosethus obtained to 2.5 to 3.5% in a 33% RH desiccator, the resultingsecond methyl cellulose was compressed and tableted at compressionpressure of 50 MPa into tablets having a tablet weight of 480 mg byusing a single-punch tableting machine (trade name “Tableting tester”,product of Sankyo Biotech). The punch was a flat punch having a diameterof 11.3 mm and having a flat contact surface. The hardness of thetablets thus obtained is shown in Table 1.

In order to have comparison with the below-mentionedhardness-unmeasurable samples due to high hardness of the tablets, thehardness was also measured for the tablets obtained at lower tabletingpressure after the adjustment of the water content of the second methylcellulose. More specifically, the second methyl cellulose was compressedand tableted at compression pressure of 30 MPa into tablets having atablet weight of 450 mg by using a desk-top type tableting machine(trade name “HANDTAB-200”, product of Ichihashi Seiki). The punch was aflat punch having a diameter of 12 mm and having a flat contact surface.The hardness of the tablets thus obtained is also shown in Table 1.

The term “water content” as used herein means a value calculated inaccordance with the following equation by using dry matter contentdetermined by the method specified in JIS P8203:1998 Determination ofDry Matter Content for Pulp.Water content (%)=100−(dry matter content) (%)In the above equation, the dry matter content is a ratio (%) of theweight of the sample dried at 105±2° C. until reaching a constant valueas the weight of the sample to the weight of the sample before dried.(Measurement Conditions)

The specific surface area by the BET (BET multipoint) method wasmeasured through a gas adsorption method (adsorption gas: nitrogen,refrigerant: liquid nitrogen) by using an automated specific surfacearea and pore distribution analyzer “TriStar II 3020” (trade name;product of Micromeritics) in accordance with the “Method 2: Thevolumetric method” of “Specific Surface Area by Gas Adsorption” inGeneral Tests described in the Japanese Pharmacopoeia 16th Edition,while keeping a relative pressure (P/P₀), wherein P₀ represents asaturated vapor pressure and P represents a measured equilibriumpressure, within a range of from 0.05 to 0.30. About 0.5 to 2 g,depending on the loose bulk density, of a sample dried at 105° C. for 2hours was used for the measurement.

When the viscosity at 20° C. of a 2% by weight aqueous solution was 600mPa·s or greater, it was measured using a single cylinder-typerotational viscometer in accordance with “Viscosity measurement byrotational viscometer” in General Tests described in the JapanesePharmacopoeia 16th Edition. When the viscosity was less than 600 mPa·s,it was measured using an Ubbelohde-type viscometer in accordance with“Viscosity measurement by capillary tube viscometer” in General Testsdescribed in the Japanese Pharmacopoeia 16th Edition.

The average particle size was measured at dispersion pressure of 2 to 3bars and scattering intensity of from 2 to 10% through laser diffraction(analysis: Fraunhofer approximation) by using “Mastersizer 3000” (tradename; product of Malvern Instruments).

The loose bulk density was measured using “Powder Tester PT-S” (tradename; product of Hosokawa Micron). A sample was fed uniformly into thecylindrical vessel (made of stainless steel) having a diameter of 5.03cm and a height of 5.03 cm (capacity: 100 ml) from 23 cm above thevessel through a JIS 22-mesh sieve (opening: 710 μm) and was weighedafter leveling off the top surface of the sample.

The tablet hardness was measured using a tablet hardness tester“TBH-125” (trade name; product of ERWEKA GmbH). A load was applied tothe diameter direction of a tablet at a rate of 1 mm/sec and the maximumbreaking strength at which the tablet was broken was measured.

Example 2

The second methyl cellulose obtained in Example 1 was ground using ahigh-speed rotating impact grinding mill, Victory Mill, equipped with ascreen of 0.3-mm openings to obtain the intended second methylcellulose. The physical properties of the resulting powder and tablethardness of tablets obtained using a single-punch tableting machine anda desk-top type tableting machine in the same manner as in Example 1 areshown in Table 1.

Example 3

The second methyl cellulose obtained in Example 2 was filtered through asieve of 38-μm openings to obtain intended second methyl cellulose. Thephysical properties of the resulting powder and tablet hardness oftablets obtained using a single-punch tableting machine and a desk-toptype tableting machine in the same manner as in Example 1 are shown inTable 1.

Example 4

The second methyl cellulose obtained in Example 1 was ground using anairflow type impact grinding mill “Jet Mill” (product of NipponPneumatic) at grind pressure of 0.35 MPa, clearance of 20 mm in theclassification zone and the louver size of “Large” to obtain theintended second methyl cellulose. The physical properties of theresulting powder and tablet hardness of tablets obtained using asingle-punch tableting machine and a desk-top type tableting machine inthe same manner as in Example 1 are shown in Table 1.

Example 5

In the same manner as in Example 1 except that depolymerization time ofthe first (high-polymerization-degree, pre-depolymerization) methylcellulose obtained in Example 1 was changed to 30 minutes, the intendedsecond methyl cellulose was obtained. The physical properties of theresulting powder and tablet hardness of tablets obtained using asingle-punch tableting machine and a desk-top type tableting machine inthe same manner as in Example 1 are shown in Table 1.

Example 6

In the same manner as in Example 1 except that depolymerization time ofthe first (high-polymerization-degree, pre-depolymerization) methylcellulose obtained in Example 1 was changed to 190 minutes, the intendedsecond methyl cellulose was obtained. The physical properties of theresulting powder and tablet hardness of tablets obtained using asingle-punch tableting machine and a desk-top type tableting machine inthe same manner as in Example 1 are shown in Table 1.

Example 7

In the same manner as in Example 4 except for using grind pressure of0.45 MPa and clearance of 35 mm in the classification zone, the intendedsecond methyl cellulose was obtained. The physical properties of theresulting powder and tablet hardness of tablets obtained using asingle-punch tableting machine and a desk-top type tableting machine inthe same manner as in Example 1 are shown in Table 1. The hardness ofthe tablets obtained using a single-punch tableting machine was so highthat the hardness was beyond the measurement limit of 500N and thusunmeasureable.

Example 8

In the same manner as in Example 4 except for using grind pressure of0.5 MPa, clearance of 35 mm in the classification zone and the louversize of “Small”, the intended second methyl cellulose was obtained. Thephysical properties of the resulting powder and tablet hardness oftablets obtained using a single-punch tableting machine and a desk-toptype tableting machine in the same manner as in Example 1 are shown inTable 1. The hardness of the tablets obtained using a single-punchtableting machine was so high that the hardness was beyond themeasurement limit of 500N and thus unmeasureable.

Comparative Example 1

The methyl cellulose reaction product was obtained in the same manner asin Example 1, washed, dried and ground using a high-speed rotatingimpact grinding mill, Victory Mill, equipped with 0.5-mm openings. Theresulting particles were filtered through a sieve of 35 μm to obtain thefirst (high-polymerization-degree, pre-depolymerization) methylcellulose. The first (high-polymerization-degree, pre-depolymerization)methyl cellulose thus obtained was depolymerized in the same manner asin Example 1 to obtain the second (low-polymerization-degree,post-depolymerization) methyl cellulose. The physical properties of theresulting powder and tablet hardness of tablets obtained using asingle-punch tableting machine and a desk-top type tableting machine inthe same manner as in Example 1 are shown in Table 1.

TABLE 1 powder properties tablet hardness specific average loosesingle-punch desk-top surface viscosity particle bulk tabletingtableting area (mPa · size density machine machine (m²/g) s) (μm) (g/mL)(N) (N) Example 1 0.75 4.18 52.1 0.27 215 136 Example 2 1.09 4.24 32.00.24 249 151 Example 3 1.32 3.61 22.0 0.25 283 167 Example 4 1.72 3.4520.8 0.22 334 202 Example 5 0.86 6.88 53.0 0.27 206 122 Example 6 0.812.65 49.0 0.26 234 142 Example 7 3.57 4.09 9.4 0.11 unmeasurable 350Example 8 6.07 3.78 4.5 0.08 unmeasurable 404 Comp. 0.44 4.25 84.2 0.24123 71 Ex. 1

It is evident from Table 1 that the methyl cellulose obtained in each ofExamples 1 to 8 shows high formability, while the methyl celluloseobtained in Comparative Example 1 is inferior in formability.Surprisingly, even when the methyl cellulose has a specific surface areaof the same level (in Examples 1, 5, and 6), the methyl cellulose hasimproved formability as its viscosity decreases.

Example 9

The methyl cellulose obtained in Example 3 was mixed for three minutesin a polyethylene bag with the components listed in the tabletcomposition below except for magnesium stearate. Then, magnesiumstearate was added thereto, mixed for 30 seconds, and tableted under thefollowing tableting conditions. The dry direct tableting method was usedto obtain tablets. The tablet hardness of the tablets thus obtained anddisintegration time (test liquid: water) in the Japanese PharmacopoeiaDisintegration Test were evaluated. The results are shown in Table 2.

Tablet Composition:

-   -   Acetaminophen fine powder (product of Yamamoto Chemical Ind.        Co., Ltd.): 50.0 parts by weight    -   Lactose hydrate (trade name “Dilactose S”; product of Freund        Corp.): 44.5 parts by weight    -   Methyl cellulose: 5.0 parts by weight    -   Light silicic anhydride: 0.5 parts by weight    -   Magnesium stearate: 0.5 parts by weight        Tableting Conditions    -   Tableting machine: rotary tableting machine (trade name “VIRGO”;        product of Kikusui Seisakusho)    -   Tablet size: 200 mg/tablet, 8 mm-D, 12 mm-R    -   Tableting pressure: 10 kN    -   Tableting speed: 20 rpm

Example 10

In the same manner as in Example 9 except for use of the methylcellulose obtained in Example 4, tablets were produced through the drydirect tableting method. The tablet hardness of the tablets thusobtained and disintegration time (test liquid: water) in the JapanesePharmacopoeia Disintegration Test were evaluated. The results are shownin Table 2.

Comparative Example 2

In the same manner as in Example 9 except for use of the methylcellulose obtained in Comparative Example 1, tablets were produced bythe dry direct tableting method. The tablet hardness of the tablets thusobtained and disintegration time (test liquid: water) in the JapanesePharmacopoeia Disintegration Test were evaluated. The results are shownin Table 2.

TABLE 2 tablet disintegration hardness (N) time (minutes) Example 9 68.59.6 Example 10 73.2 9.1 Comp. Ex. 2 40.3 6.5

It is evident from Table 2 that the tablets obtained in Examples 9 and10 by the dry direct tableting method had higher tablet hardness thanthat of tablets obtained in Comparative Example 2. On the other hand,significant delay in disintegration time was not observed.

Example 11

Using the methyl cellulose obtained in Example 3, the powder having thefollowing composition was dry granulated with “Roller Compactor MINI”(trade name; product of Freund Corporation) at roll pressure of 6 MPa, aroll rotation speed of 4 rpm, and a screw rotation speed of 5 rpm.

Composition of Ground Powders

-   -   Acetaminophen fine powder (product of Yamamoto Chemical Ind.        Co., Ltd.): 10.0 parts by weight    -   Lactose hydrate (trade name “Pharmatose 200M”; product of DFE        Pharma): 79.0 parts by weight    -   Methyl cellulose: 10.0 parts by weight    -   Light silicic anhydride: 0.5 parts by weight    -   Magnesium stearate: 0.5 parts by weight

To the granulated product was further added 0.5 parts by weight ofmagnesium stearate. The resulting mixture was mixed for 30 seconds, andtableted under the following tableting conditions to obtain tablets. Thetablet hardness of the tablets thus obtained is shown in Table 3.

Tableting Conditions

-   -   Tableting machine: rotary tableting machine (trade name “VIRGO”;        product of Kikusui Seisakusho)    -   Tablet size: 200 mg/tablet, 8 mm-D, 12 mm-R    -   Tableting pressure: 10 kN    -   Tableting speed: 20 rpm

Example 12

After dry granulation in the same manner as in Example 11 except for useof the methyl cellulose obtained in Example 4, the granulated powder wastableted into tablets. The tablet hardness of the tablets thus obtainedis shown in Table 3.

Comparative Example 3

After dry granulation in the same manner as in Example 11 except for useof the methyl cellulose obtained in Comparative Example 1, thegranulated powder was tableted into tablets. The tablet hardness of thetablets thus obtained is shown in Table 3.

TABLE 3 tablet hardness (N) Example 11 50.5 Example 12 56.9 Comp. Ex. 334.2

It is evident from Table 3 that the preparations obtained in Examples 11and 12 by dry granulation tableting method had tablet hardness higherthan that in Comparative Example 3.

The invention claimed is:
 1. A method for producing methyl cellulose foruse in tableting, the methyl cellulose having a specific surface area offrom 0.5 to 10.0 m²/g as measured by BET method, and the methodcomprising the steps of: bringing pulp into contact with an alkali metalhydroxide solution to obtain alkali cellulose, reacting the alkalicellulose with an etherifying agent to obtain first methyl cellulose,pulverizing the first methyl cellulose, and depolymerizing thepulverized first methyl cellulose through hydrolysis in the presence ofan acid catalyst or through oxidative decomposition in the presence ofan oxidant to obtain second methyl cellulose, and pulverizing the secondmethyl cellulose.
 2. The method for producing methyl cellulose for usein tableting according to claim 1, wherein the acid catalyst compriseshydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, orcombinations thereof.
 3. The method for producing methyl cellulose foruse in tableting according to claim 1, wherein second methyl celluloseis water-soluble.
 4. The method for producing methyl cellulose for usein tableting according to claim 1, wherein the etherifying agent ismethyl chloride.
 5. The method for producing methyl cellulose for use intableting according to claim 1, wherein a 2% by weight aqueous solutionof the second methyl cellulose has a viscosity 20° C. from 1 to 15 mPas.6. The method for producing methyl cellulose for use in tabletingaccording to claim 1, wherein an aqueous solution of the second methylcellulose has a viscosity at 20° C. that is from 2.5 to 4.5 mPas.
 7. Themethod for producing methyl cellulose for use in tableting according toclaim 1, wherein the second methyl cellulose has an average particlesize of from 1 to 120 μm.
 8. The method for producing methyl cellulosefor use in tableting according to claim 1, wherein the second methylcellulose has an average particle size is from 10 to 30 μm.
 9. Themethod for producing methyl cellulose for use in tableting according toclaim 1, wherein the second methyl cellulose has a loose bulk density offrom 0.01 to 0.50 g/mL.
 10. The method for producing methyl cellulosefor use in tableting according to claim 1, wherein the second methylcellulose has a loose bulk density of from 0.2 to 0.4 g/mL.
 11. Themethod for producing methyl cellulose for use in tableting according toclaim 1, wherein the second methyl cellulose has a specific surface areathat is from 1.2 to 2.0 m²/g as measured by BET method.
 12. The methodfor producing methyl cellulose for use in tableting according to claim1, wherein following the step of pulverizing, the first methyl has anaverage particle size of from 10 to 200 μm.
 13. The method for producingmethyl cellulose for use in tableting according to claim 1, whereinfollowing the step of pulverizing, the first methyl has an averageparticle size of from 10 to 120 μm.
 14. The method for producing methylcellulose for use in tableting according to claim 1, wherein the step ofdepolymerizing the pulverized first methyl cellulose is performed at atemperature from 50 to 130° C.
 15. The method for producing methylcellulose for use in tableting according to claim 1, further comprisinga step of tableting the second methyl cellulose with a drug, and one ormore of an excipient, a disintegrant, a binder, anaggregation-preventing agent and a solubilizing agent.